Overcoming problems of poor drug penetration into bacteria: challenges and strategies for medicinal chemists

Bacterial cell walls and membranes provide essential protection for bacteria against environmental influences. Different bacteria possess different cell envelopes and understanding each of these structures is crucial for the design of effective antibacterial drugs whose targets are intracellular. Optimal properties of drugs that are required for their entry into bacteria are still hard to predict. The guidelines that are suitable and well established for the penetration of a drug into eukaryotic cells are poorly adaptable to the complex world of pathogens. Areas covered: The factors that govern the penetration of anti-infection drugs into bacteria are examined and the available strategies to overcome this therapeutically very important barrier are reviewed. The areas covered include optimization of the physicochemical properties of compounds, utilization of iron-chelating compounds, i.e. siderophores, the use of efflux pump inhibitors, and of carriers such as liposomes. Expert opinion: Although several rules governing permeation have recently been proposed for effective antibacterial drugs, none of them has been so far established as the 'golden' rule. Thus, new research is needed to find a more general approach on how to increase the concentration of antibacterial compounds in bacterial cells.